If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China
Corresponding author. Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China.
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, 230026, ChinaCenter for Excellence in Molecular Synthesis of Chinese Academy of Sciences, Hefei, 230026, China
An enantio- and diastereodivergent [2+2+1] annulation reaction of allyl ketones, acidic methylene compounds, and nitroalkenes to assemble highly functionalized cyclopentanes from readily available substances enabled by asymmetric relay catalysis of chiral bifunctional squaramide and palladium complex has been established. This method showcases that allyl ketones can serve as latent 1,2-dication synthons via a linear-selective allylic C–H functionalization and sequential 1,4-conjugated addition, enabling the rapid assembly of cyclopentane skeleton with a broad scope of methylene nucleophiles and nitroalkenes. Notably, chiral bifunctional squaramide catalyst engages in both the intermolecular and intramolecular Michael addition reactions accompanying with a kinetic resolution behavior to amplify the enantioselection. In addition, the stereodivergent synthesis of diastereomers from the resultant chiral cyclopentane derivatives is also accessible by a simple manipulation with base.
Chiral cyclopentane is a fundamental structural motif ubiquitously presented in a huge number of naturally occurring and medicinally relevant compounds [
], and therefore the asymmetric catalytic synthesis of polysubstituted five-membered carbon rings has been continuously receiving long-standing interest to organic chemists [
], have been successfully established for the stereoselective synthesis of five-membered rings with multi-stereogenic centers (Fig. 1a). Instead of proceeding through one- or two-component processes, the multi-component [2+2+1] annulation, closely related to the Pauson–Khand synthesis of cyclopentenones [
], is undoubtedly one of the most appealing and straightforward methods to rapidly assemble functionalized cyclopentanes from simple and readily available starting materials in a single operation (Fig. 1a). However, the scarcity of conventional 1,2-dication synthons makes chemo-, regio-, and stereoselective [2+2+1] annulations for the synthesis of multi-substituted chiral cyclopentanes generally toughly accessible.
Fig. 1Methods to access chiral cyclopentanes. a, Commonly used methods to access chiral cyclopentanes. b, Asymmetric [2+2+1] annulation enabled by the combination of chiral organocatalysis and palladium catalysis (this work).
] can enable the C–C double bond of allyl ketones to serve as latent 1,2-dication synthons, which are able to participate in an asymmetric [2+2+1] annulation reaction with acidic methylene compounds and nitroalkenes to provide highly functionalized cyclopentane skeleton with three continuous stereogenic centers (Fig. 1b), and in particular, the diastereoisomers can also be smoothly obtained by a simple manipulation with K3PO4 as a base.
The design plan of evaluating α-alkenes as 1,2-dication synthons stems from our previous work on the Pd-catalyzed asymmetric allylic C–H cleavage [
Chiral counteranion strategy for asymmetric oxidative C(sp3)-H/C(sp3)-H coupling: enantioselective alpha-allylation of aldehydes with terminal alkenes.
Highly enantioselective allylic C-H alkylation of terminal olefins with pyrazol-5-ones enabled by cooperative catalysis of palladium complex and Brønsted acid.
] and the subsequent nucleophile attack at the terminus of this intermediate results in the generation of an α,β-unsaturated ketone capable of being attacked by another nucleophile (Fig. 2). In this regard, allyl ketones can serve as latent 1,2-dication synthons via a sequential linear-selective allylic C–H alkylation and 1,4-conjugate addition. On the other hand, the past two decades have also witnessed significant progress in the organocatalytic asymmetric conjugate addition of nucleophiles to Michael acceptors [
] inspired us to select this organocatalytic asymmetric Michael addition as an approach to access chiral 1,3-dianion synthon from barbituric acid 1 and nitroalkene 2. Then, the resulting Michael adduct 4 would undergo a chemo- and regioselective Pd-catalyzed allylic C–H alkylation [
] with allyl ketone 3 to provide an allylation product 5, which would finally participate in an intramolecular asymmetric Michael addition to deliver the desired densely functionalized cyclopentane derivative 6. This cascade process enables the enantioenriched cyclopentane skeleton to be rapidly assembled from easily accessible barbituric acid 1 (C-1 synthon), nitroalkene 2 (C-2 synthon) and allyl ketone 3 (C-2 synthon).
Fig. 2Mechanistic analysis of the allyl ketone to serve as latent 1,2-dication synthon in asymmetric [2+2+1] annulation.
However, some issues are requisitely addressed to establish this targeted process, including: (1) the palladium complex should be compatible with chiral bifunctional organocatalyst under the oxidative conditions to enable the cascade reaction; (2) the stereoselectivity of the final intramolecular Michael addition must be controlled by the newly formed stereogenic centers in the previous steps, chiral bifunctional organocatalyst, or both; (3) the reaction rate of each individual step should be precisely leveraged to minimize all possible side reactions, such as bis-Michael addition of barbituric acid to nitroalkene and the bis-allylation of barbituric acid [
Reaction development. The validation of the proposed [2+2+1] annulation reaction of barbituric acid 1, β-nitrostyrene 2, and allyl ketone 3 started with the evaluation of chiral bifunctional organocatalysts and palladium-phosphoramidite catalysts by using 2,5-dimethyl-p-benzoquinone (2,5-DMBQ) as an oxidant (Table 1 and Tables S1–S2). We found that the presence of chiral bifunctional organocatalyst C1 and the palladium complex of phosphoramidite L1 smoothly enabled the reaction to provide the desired cyclopentane 6 in 23% yield with 94:6 d.r. and 68% e.e. at room temperature (Table 1, entry 1). The 1H NMR analysis of the crude reaction mixture identified that the initial asymmetric Michael addition and the subsequent allylic C–H alkylation proceeded readily, while the final intramolecular Michael addition underwent much more slowly. To speed up the last step in this relay catalytic cascade process, the reaction temperature was elevated. Indeed, a stepwise upregulation of reaction temperature (25 °C–70 °C) did significantly enhance the yield, albeit with relatively lower stereoselectivities (entry 2). Fine modulation of the hydrogen-bonding scaffold on the bifunctional organocatalysts [
] was superior to other counterparts in terms of stereoselectivity (entries 3–4). Notably, the alteration of the dimethylamine moiety to a piperidine group obviously enhanced the enantio-induction (entry 5).
Table 1Optimization of reaction conditions.
Table 1Optimization of reaction conditions.
Reaction conditions: 1 (0.1 mmol), 2 (0.105 mmol), 3 (0.11 mmol), C (0.002 mmol), Pd2(dba)3 (0.0025 mmol), L (0.006 mmol), 2,5-DMBQ (0.11 mmol), toluene (1.0 mL), under nitrogen, at 25 °C for 1.5 h, and then at 70 °C for 12 h. The yield and diastereoselectivity were determined via 1H NMR analysis using trimethyl 1,3,5-benzenetricarboxylate as an internal standard, and the e.e. value was determined by HPLC using a chiral stationary phase. The absolute configuration of 6 and 7 was assigned by analogy. N.D. = not detected. aPerformed at 25 °C for 13.5 h. b(1R,2R,3S)-6 and (1S,2S,3S)-7 were preferentially generated. cWithout Pd2(dba)3. dWith 1 mol% C4 and 0.5 mL toluene. eIsolated yield. Bz = benzoyl.
] examined, those incorporated with the cyclic amine moiety performed better in terms of both efficiency and stereoselectivity (entry 6), but 3,3′-disubstitution on the biphenol moiety was unable to further improve the reaction performance (entry 7). Interestingly, the absence of phosphoramidite ligand still gave the desired cyclopentane 6 but with very poor efficiency (entry 8). The 1H NMR analysis of the reaction process revealed that although almost all barbituric acid 1 was converted to the Michael addition product 4, the subsequent allylation product 5 was rarely detected, confirming that the presence of phosphoramidite ligand greatly accelerated the Pd-catalyzed allylic C–H alkylation [
], wherein the allylic C–H bond cleavage occurred via a concerted proton and two-electron transfer process mediated with an active 16-electron Pd(0) complex bearing a phosphoramidite ligand, a benzoquinone, and an alkene [
]. The absence of either the palladium or chiral bifunctional squaramide catalysts was unable to allow this three-component annulation reaction undergoing (entries 9–10). Ultimately, excellent results of 98% yield, 94:6 d.r. and 96% e.e. were obtained at a higher concentration and a halved amount of chiral squaramide catalyst C4 (entry 11).
Reaction Scope. With the optimized conditions in hand, the generality of the three-component annulation reaction was examined. As shown in Fig. 3, a wide range of substituted nitrostyrenes bearing either electron-rich or electron-deficient substituents at the para-, meta-, or ortho-position of benzene ring were well tolerated to afford the corresponding annulation products (8-17) in good to excellent yields and with high levels of stereoselectivity. Moreover, nitroalkenes substituted with naphthyl and heteroaryls were excellent substrates to smoothly undergo the annulation reaction with excellent enantioselectivity (18–20), but the alkenyl-substituted nitroalkene resulted in a poor diastereoselectivity (21). It is worth noting that the reaction involving either aliphatic nitroalkenes (22–23) or β-ester substituted nitroalkene (24) also proceeded well. Next, we turned our attention to the allyl ketone component. A variety of electron-rich and electron-deficient substitutions on the benzene ring of phenyl allyl ketones could be employed while retaining good to excellent efficiency and stereoselectivity (25–30). Additionally, heteroaryl allyl ketones were viable substrates, providing the desired chiral cyclopentanes (31–33) in good to excellent yields and with excellent enantioselectivities. Furthermore, alkyl allyl ketones could also participate in the desired three-component annulation with high levels of stereochemical control. For instance, vinylacetic ester, vinylacetic amide and allylnitrile underwent this formal [2+2+1] annulation reaction with good results (39–41). Finally, we examined this three-component reaction with other types of active methylene compounds. Both N-cyclohexyl and N-phenyl substituted barbituric acids turned out to be suitable nucleophiles (42–43). By means of the re-optimized chiral squaramide bifunctional catalyst C5, Meldrum's acid, a valuable and widely used building block in organic synthesis arisen from its high acidity and versatile synthetic utility [
], was also found to be applicable to yield the desired product (44) with excellent stereoselectivity. The absolute configuration of 11 and 44 were determined by X-ray crystallographic analysis (Fig. 3).
Fig. 3Scope of the [2+2+1] annulation reaction. Reaction conditions: active methylene compound (0.1 mmol), nitroalkene (0.105 mmol), α-alkene (0.11 mmol), C4 (0.001 mmol), Pd2(dba)3 (0.0025 mmol), L2 (0.006 mmol), 2,5-DMBQ (0.11 mmol), toluene (1.0 mL), under nitrogen. The reaction mixture was stirred at 25 °C for 1.5 h, then at 70 °C for 12 h. Isolated Yield. The d.r. was determined by 1H NMR analysis of the crude products. The e.e. was determined by HPLC analysis. The absolute stereochemistry was assigned by analogy. aPerformed with 2 mol% C4. bPerformed at 25 °C for 1.5 h, then at 80 °C for 12 h cPerformed at 25 °C for 1.5 h, then at 70 °C for 24 h dPerformed at 25 °C for 1.5 h, at 70 °C for 12 h, then at 120 °C for 2 h ePerformed with 5 mol% C5.
Interestingly, the exposure of the resulting reaction mixture of barbituric acid 1, β-nitrostyrene 2, and allyl ketone 3 to K3PO4 at 70 °C for additional 12 h smoothly enabled the configuration of the C-2 and C-3 to be inversed (Table S3 and Fig. 4), leading to a thermodynamically more stable cyclopentane 7 as the major diastereoisomer with slightly diminished enantioselectivity in comparison with that of 6 (87% e.e. vs 96% e.e.). Notably, the treatment of 6 with K3PO4/D2O at 70 °C for 12 h afforded a monodeuterated product 7-d1 with 82% deuteration at the C-3 position, suggesting that the transformation of 6 to 7 might proceed through a multi-step process consisting of base-mediated deprotonation at the C-3 to form α-nitro carbanion I, the subsequent C–C cleavage via a retro-Michael addition to give nitroalkene II, a Michael addition-mediated reformation of C–C bond to generate α-nitro carbanion III, and a protonation of carbanion to provide 7. In addition, such a configuration switching process was applicable to a series of nitroalkenes and aryl allyl ketones, furnishing the desired products (45–49) in moderate to high yields and with synthetically acceptable stereoselectivities.
Fig. 4Diastereodivergent synthesis. Reaction conditions: barbituric acid (0.1 mmol), nitroalkene (0.105 mmol), allyl ketone (0.11 mmol), C4 (0.001 mmol), Pd2(dba)3 (0.0025 mmol), L2 (0.006 mmol), 2,5-DMBQ (0.11 mmol), and toluene (1.0 mL), under nitrogen. The reaction mixture was stirred at 25 °C for 1.5 h and 70 °C for 12 h, then K3PO4 (0.16 mmol) and H2O (0.2 mmol) were added, and then the reaction was carried out at 70 °C for another 12 h. Isolated yield based on analytically pure products. The diastereoselectivity was determined via 1H NMR analysis, and the e.e. value was determined by HPLC using a chiral stationary phase.
This three-component annulation protocol is practical and synthetically useful. A gram scale reaction of barbituric acid 1, nitroalkene 50 and allyl ketone 3 performed well under a slightly modified conditions to furnish the desired annulation product 11 without a notable decrease in efficiency and stereoselectivity (Fig. 5a). The hydrogenation of the annulation product 39 under the Raney-Ni catalysis resulted in the reduction of the nitro group and subsequent intramolecular amidation, giving rise to a fused bicyclic lactam derivative 51 in 63% yield with maintained diastereoselectivity (Fig. 5b). Interestingly, the treatment of 39 with Pd/C catalyst under hydrogen atmosphere was able to undergo chemospecific hydrogenolysis of benzyl ester to generate a carboxylic acid product 52. Moreover, the malonate derivative 44 was smoothly converted to an enantioenriched cyclopentane 54 with four stereocenters by hydrolysis and amidation, albeit with a poor diastereoselectivity (Fig. 5c).
Fig. 5Synthetic applications. a. Gram scale reaction. b. Transformations of the annulation product 39. c. Transformations of the annulation product 44. RT = room temperature.
To gain insights into the possible reaction mechanism, a series of kinetic studies and control experiments were conducted. Firstly, the progress curve of this three-component annulation reaction (Fig. 6a and Table S4) showed that the initial intermolecular Michael addition of barbituric acid 1 to β-nitrostyrene 2 proceeded very fast at room temperature and was completed within 20 min to provide the corresponding Michael adduct 4 (blue curve), meanwhile the sequential allylation of 4 with allyl ketone 3 also underwent smoothly at room temperature to afford the allylation product 5 (orange curve). However, the final annulation via intramolecular Michael addition failed to proceed at room temperature. Instead, the formation of the desired cyclopentane derivative 6 was facilitated upon warming up the reaction to 70 °C (red curve). Secondly, very similar results were obtained for the intermolecular Michael addition of barbituric acid 1 to nitroalkene 2 in the absence and presence of the palladium catalyst (Table S5), suggesting that the enantioselective intermolecular Michael addition was merely facilitated by chiral squaramide catalyst, even though a non-stereoselective Michael addition proceeded sluggishly in the presence of the palladium catalyst alone (Fig. 6b). Moreover, the reaction of allyl ketone 3 and Michael addition adduct 4 in the absence and presence of chiral squaramide catalyst C4 showed very similar reaction rates at 25 °C based on the kinetic profiles (Fig. 6c and Tables S6–S7), implying that the chiral squaramide catalyst C4 was unlikely to participate in the Pd-catalyzed allylic C–H alkylation reaction. Finally, the reaction of 3 and 4 with the palladium catalyst alone at 70 °C merely gave rise to the allylation product 5, but were unable to generate the final annulation product 6 (Fig. 6c). Moreover, the reaction of 3 and enantioenriched 4 (87% e.e.) under the combined catalysis of the palladium complex and chiral squaramide C4 smoothly afforded the desired cyclopentane 6 with an enhanced enantioselectivity (94% e.e.), and in particular, the treatment of 3 with racemic 4 under the otherwise identical conditions was able to furnish 6 with 49% e.e. and 7 with 98% e.e., respectively. These results suggest that only chiral squaramide catalyst C4 engages in the final annulation process accompanying with a kinetic resolution behavior to amplify the enantioselection.
Fig. 6Mechanistic insights into the [2+2+1] annulation. a. Progress curve of the three-component annulation reaction. b, Evaluating of palladium catalyst on the intermolecular Michael addition. c, Evaluating of bifunctional squaramide C4 on the allylic C–H alkylation and subsequent annulation. aThe e.e was determined after chlorination.
In summary, we have established an enantio- and diastereodivergent [2+2+1] annulation reaction to assemble highly functionalized cyclopentanes from readily available substances enabled by the combination of chiral bifunctional squaramide organocatalysis and palladium catalysis. This method showcases that the allyl ketones are capable of serving as latent 1,2-dication synthons via a linear-selective allylic C–H functionalization and sequential 1,4-conjugated addition, enabling the rapid assembly of cyclopentane skeleton with a broad scope of methylene nucleophiles and nitroalkenes. Notably, chiral bifunctional squaramide catalyst engages in both the intermolecular and intramolecular Michael addition reactions accompanying with a kinetic resolution behavior to amplify the enantioselection. In addition, the stereodivergent synthesis of the diastereomers from the resulting chiral cyclopentane derivatives is also accessible by a simple manipulation with base. Notably, the findings will promote the future development of Pd-catalyzed asymmetric allylic C–H functionalization reactions.
4. Experimental procedures
4.1 Resource availability
4.1.1 Lead contact
Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Liu-Zhu Gong ([email protected]).
4.1.2 Materials availability
This study did not generate new materials.
4.1.3 Data and code availability
The crystallography data have been deposited at the Cambridge Crystallographic Data Center (CCDC) as CCDC-2104248 (11), 2104250 (44) and 2107057 (45) can be obtained free of charge from www.ccdc.cam.ac.uk/getstructures.
Full experimental procedures are provided in the Supplemental Information.
Author contributions
L.-F. F. and R. L. performed the three-component annulation methodology and experimental mechanistic study. P.-S. W. and L.-Z. G. conceived and supervised the project. All authors analyzed the data and wrote the manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The financial support from the NSFC (21831007 and 21672197), Anhui Provincial Natural Science Foundation (2108085MB58) and Youth Innovation Promotion Association CAS, is gratefully acknowledged.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Chiral counteranion strategy for asymmetric oxidative C(sp3)-H/C(sp3)-H coupling: enantioselective alpha-allylation of aldehydes with terminal alkenes.
Highly enantioselective allylic C-H alkylation of terminal olefins with pyrazol-5-ones enabled by cooperative catalysis of palladium complex and Brønsted acid.
☆Professor Liu-Zhu Gong, the corresponding author on this paper is a member of the advisory board but this author had no involvement in the peer review process used to assess this work submitted to Tetrahedron Chem. This paper was assessed and the corresponding peer review managed by Dr Chaosheng Luo, a scientific editor working on Tetrahedron Chem.
00002-4&id=ga1.jpg){kind=link}
00002-4&id=gr1.jpg){kind=link}
00002-4&id=gr2.jpg){kind=link}
00002-4&id=gr3.jpg){kind=link}
00002-4&id=gr4.jpg){kind=link}
00002-4&id=gr5.jpg){kind=link}
00002-4&id=gr6.jpg){kind=link}